FASD (Fetal Alcohol Spectrum Disorder) is a debilitating disease that encompasses all ethanol-induced defects and diseases. It is estimated to affect over 1% of children born in the United States, with defects affecting the brain and craniofacial skeleton. Although fetal exposure to ethanol causes FASD, genetic factors may contribute as well. A novel screen was used to identify gene/ethanol interactions to understand how gene/ethanol interactions may influence disease variation and severity. By screening available zebrafish craniofacial mutants, platelet derived growth factor receptor a (pdgfra) and fibroblast growth factor 8a (fgf82) were identified as ethanol sensitive loci. Preliminary data suggests that a common mechanism of interaction occurs in the PI3K/AKT/mTOR pathway, which is known to promote cell survival signals.The etiology of defects found in the pdgfra interaction have been thoroughly described, and further assessment of the fgf8a/ethanol interaction are needed. The purpose of this proposal is to test the hypothesis that gene/ethanol interactions influence variability and severity found in FASD. Three aims will encompass testing this hypothesis and include: 1) Analyzing the mechanism of gene/ethanol interaction through immunoblot assays of enzymes in the PI3K/AKT/mTOR pathway in both mutants;2) Describing the ethanol/fgf8a craniofacial defects through in situ expression analysis and transplantation experiments, and 3) Elucidating fgf8a haploinsufficiency in neural defects, and how timing of ethanol-exposure exacerbates the severity of these defects. The results from these aims will have significant impact in the field of ethanol teratology, providing novel insight into both the genetic modulation and mechanism of interaction involved in the etiology of ethanol induced disease. This will further promote advancements in genetic counseling, diagnosis and treatment of FASD. PUBLIC HEALTH RELEVANCE: The purpose of this proposal is to seek the underlying genetic loci that cause the variability of defects found in patients with Fetal Alcohol Spectrum Disorder (FASD). Results obtained from this proposal will greatly increase our understanding of gene/environment interactions and the etiology of this debilitating disease. This will further advance efforts in genetic counseling, diagnosis and treatment of FASD.